Evidence for spreading seizure as a cause of theta-alpha activity electrographic pattern in stereo-EEG seizure recordings.

Intracranial electroencephalography is a standard tool in clinical evaluation of patients with focal epilepsy. Various early electrographic seizure patterns differing in frequency, amplitude, and waveform of the oscillations are observed. The pattern most common in the areas of seizure propagation is the so-called theta-alpha activity (TAA), whose defining features are oscillations in the θ - α range and gradually increasing amplitude. A deeper understanding of the mechanism underlying the generation of the TAA pattern is however lacking. In this work we evaluate the hypothesis that the TAA patterns are caused by seizures spreading across the cortex. To do so, we perform simulations of seizure dynamics on detailed patient-derived cortical surfaces using the spreading seizure model as well as reference models with one or two homogeneous sources. We then detect the occurrences of the TAA patterns both in the simulated stereo-electroencephalographic signals and in the signals of recorded epileptic seizures from a cohort of fifty patients, and we compare the features of the groups of detected TAA patterns to assess the plausibility of the different models. Our results show that spreading seizure hypothesis is qualitatively consistent with the evidence available in the seizure recordings, and it can explain the features of the detected TAA groups best among the examined models.

Data-driven method to infer the seizure propagation patterns in an epileptic brain from intracranial electroencephalography.

Surgical interventions in epileptic patients aimed at the removal of the epileptogenic zone have success rates at only 60-70%. This failure can be partly attributed to the insufficient spatial sampling by the implanted intracranial electrodes during the clinical evaluation, leading to an incomplete picture of spatio-temporal seizure organization in the regions that are not directly observed. Utilizing the partial observations of the seizure spreading through the brain network, complemented by the assumption that the epileptic seizures spread along the structural connections, we infer if and when are the unobserved regions recruited in the seizure. To this end we introduce a data-driven model of seizure recruitment and propagation across a weighted network, which we invert using the Bayesian inference framework. Using a leave-one-out cross-validation scheme on a cohort of 45 patients we demonstrate that the method can improve the predictions of the states of the unobserved regions compared to an empirical estimate that does not use the structural information, yet it is on the same level as the estimate that takes the structure into account. Furthermore, a comparison with the performed surgical resection and the surgery outcome indicates a link between the inferred excitable regions and the actual epileptogenic zone. The results emphasize the importance of the structural connectome in the large-scale spatio-temporal organization of epileptic seizures and introduce a novel way to integrate the patient-specific connectome and intracranial seizure recordings in a whole-brain computational model of seizure spread.

Connectivity Alterations in Emotional and Cognitive Networks During a Manic State Induced by Direct Electrical Stimulation.

Mania is characterized by affective and cognitive alterations, with heightened external and self-awareness that are opposite to the alteration of awareness during epileptic seizures. Electrical stimulations carried out routinely during stereotactic intracerebral EEG (SEEG) recordings for presurgical evaluation of epilepsy may represent a unique opportunity to study the pathophysiology of such complex emotional-behavioral phenomenon, particularly difficult to reproduce in experimental setting. We investigated SEEG signals-based functional connectivity between different brain regions involved in emotions and in consciousness processing during a manic state induced by electrical stimulation in a patient with drug-resistant focal epilepsy. The stimulation inducing manic state and an asymptomatic stimulation of the same site, as well as a seizure with alteration of awareness (AOA) were analyzed. Functional connectivity analysis was performed by measuring interdependencies (nonlinear regression analysis based on the h2 coefficient) between broadband SEEG signals and within typical sub-bands, before and after stimulation, or before and during the seizure with AOA, respectively. Stimulation of the right lateral prefrontal cortex induced a manic state lasting several hours. Its onset was associated with significant increase of broadband-signal functional coupling between the right hemispheric limbic nodes, the temporal pole and the claustrum, whereas significant decorrelation between the right lateral prefrontal and the anterior cingulate cortex was observed in theta-band. In contrast, ictal alteration of awareness was associated with increased broadband and sub-bands synchronization within and between the internal and external awareness networks, including the anterior and middle cingulate, the mesial and lateral prefrontal, the inferior parietal and the temporopolar cortex. Our data suggest the existence of network- and frequency-specific functional connectivity patterns during manic state. A transient desynchronization of theta activity between the external and internal awareness network hubs is likely to increase awareness, with potential therapeutic effect.

Illusory own body perceptions mapped in the cingulate cortex-An intracranial stimulation study.

Body awareness is the result of sensory integration in the posterior parietal cortex; however, other brain structures are part of this process. Our goal is to determine how the cingulate cortex is involved in the representation of our body. We retrospectively selected patients with drug-resistant epilepsy, explored by stereo-electroencephalography, that had the cingulate cortex sampled outside the epileptogenic zone. The clinical effects of high-frequency electrical stimulation were reviewed and only those sites that elicited changes related to body perception were included. Connectivity of the cingulate cortex and other cortical structures was assessed using the h2 coefficient, following a nonlinear regression analysis of the broadband EEG signal. Poststimulation changes in connectivity were compared between two sets of stimulations eliciting or not eliciting symptoms related to body awareness (interest and control groups). We included 17 stimulations from 12 patients that reported different types of body perception changes such as sensation of being pushed toward right/left/up, one limb becoming heavier/lighter, illusory sensation of movement, sensation of pressure, sensation of floating or detachment of one hemi-body. High-frequency stimulation in the cingulate cortex (1 anterior, 15 middle, 1 posterior part) elicits body perception changes, associated with a decreased connectivity of the dominant posterior insula and increased coupling between other structures, located particularly in the nondominant hemisphere.

Hypothalamic hamartoma: Epileptogenesis beyond the lesion?

The discovery of intrinsic epileptogenicity of the hypothalamic hamartoma (HH) marked a new area in understanding the associated clinical syndrome, often manifesting as progressive epileptic encephalopathy. However, therapeutic procedures targeting the HH proved to be inefficient to cure seizures in up to 50% of cases, whereas in cases with partial improvement, the electroclinical patterns of persisting seizures suggest an involvement of distant cortical regions. The concept of kindling-like secondary epileptogenesis has been suggested as a possible underlying mechanism. Yet the role of the hypothalamic lesion in the pathophysiology of the syndrome remains debatable. In the Strasbourg-Kork series, the best outcomes were obtained when the duration of epilepsy before endoscopic HH surgery did not exceed 10 years. In two patients with HH ablation followed at a later time by a temporal lobectomy, only this second surgical step allowed complete seizure freedom. These findings suggest the existence of an independent, third stage of secondary epileptogenesis in human. In the Grenoble series, stereotactic intracerebral recordings (stereo electroencephalography [SEEG]) of five HH cases demonstrated that gelastic/dacrystic seizures were correlated with discharges within the HH, whereas other seizure types were related to discharges affecting cortical regions, which sometimes seemed to be triggered by HH. In the Marseille series, two cases explored by SEEG provided evidence of extended epileptogenicity outside the limits of the HH, forming complex epileptogenic networks, with HH still triggering clusters of neocortical seizures in the first, but not obligatory involved in spontaneous seizures in the second case. Taken together, our data argue for the existence of dynamic ictal network organization, with possible "kindling-like" relationships between the HH and the neocortex or widespread epileptogenesis. Despite the existence of secondary epileptogenesis, the epileptogenic zone could still be limited to the hamartoma, for which early surgical treatment should be pragmatically considered as a first surgical step.

Epileptogenic networks in nodular heterotopia: A stereoelectroencephalography study.

OBJECTIVE: Defining the roles of heterotopic and normotopic cortex in the epileptogenic networks in patients with nodular heterotopia is challenging. To elucidate this issue, we compared heterotopic and normotopic cortex using quantitative signal analysis on stereoelectroencephalography (SEEG) recordings. METHODS: Clinically relevant biomarkers of epileptogenicity during ictal (epileptogenicity index; EI) and interictal recordings (high-frequency oscillation and spike) were evaluated in 19 patients undergoing SEEG. These biomarkers were then compared between heterotopic cortex and neocortical regions. Seizures were classified as normotopic, heterotopic, or normoheterotopic according to respective values of quantitative analysis (EI ≥0.3). RESULTS: A total of 1,246 contacts were analyzed: 259 in heterotopic tissue (heterotopic cortex), 873 in neocortex in the same lobe of the lesion (local neocortex), and 114 in neocortex distant from the lesion (distant neocortex). No significant difference in EI values, high-frequency oscillations, and spike rate was found comparing local neocortex and heterotopic cortex at a patient level, but local neocortex appears more epileptogenic (p < 0.001) than heterotopic cortex analyzing EI values at a seizure level. According to EI values, seizures were mostly normotopic (48.5%) or normoheterotopic (45.5%); only 6% were purely heterotopic. A good long-term treatment response was obtained in only two patients after thermocoagulation and surgical disconnection. SIGNIFICANCE: This is the first quantitative SEEG study providing insight into the mechanisms generating seizures in nodular heterotopia. We demonstrate that both the heterotopic lesion and particularly the normotopic cortex are involved in the epileptogenic network. This could open new perspectives on multitarget treatments, other than resective surgery, aimed at modifying the epileptic network.

Current use of imaging and electromagnetic source localization procedures in epilepsy surgery centers across Europe.

OBJECTIVE: In 2014 the European Union-funded E-PILEPSY project was launched to improve awareness of, and accessibility to, epilepsy surgery across Europe. We aimed to investigate the current use of neuroimaging, electromagnetic source localization, and imaging postprocessing procedures in participating centers. METHODS: A survey on the clinical use of imaging, electromagnetic source localization, and postprocessing methods in epilepsy surgery candidates was distributed among the 25 centers of the consortium. A descriptive analysis was performed, and results were compared to existing guidelines and recommendations. RESULTS: Response rate was 96%. Standard epilepsy magnetic resonance imaging (MRI) protocols are acquired at 3 Tesla by 15 centers and at 1.5 Tesla by 9 centers. Three centers perform 3T MRI only if indicated. Twenty-six different MRI sequences were reported. Six centers follow all guideline-recommended MRI sequences with the proposed slice orientation and slice thickness or voxel size. Additional sequences are used by 22 centers. MRI postprocessing methods are used in 16 centers. Interictal positron emission tomography (PET) is available in 22 centers; all using 18F-fluorodeoxyglucose (FDG). Seventeen centers perform PET postprocessing. Single-photon emission computed tomography (SPECT) is used by 19 centers, of which 15 perform postprocessing. Four centers perform neither PET nor SPECT in children. Seven centers apply magnetoencephalography (MEG) source localization, and nine apply electroencephalography (EEG) source localization. Fourteen combinations of inverse methods and volume conduction models are used. SIGNIFICANCE: We report a large variation in the presurgical diagnostic workup among epilepsy surgery centers across Europe. This diversity underscores the need for high-quality systematic reviews, evidence-based recommendations, and harmonization of available diagnostic presurgical methods.

First description of pharmacoresistant epilepsy due to independent bilateral hypothalamic hamartomas.

Hypothalamic hamartomas (HHs) are rare developmental malformations consisting of mixed neurons and glial cells, usually unilaterally attached to the tuber cinereum or mammillary bodies. We report on two patients, both suffering from pharmacoresistant epilepsy, behavioural and cognitive disturbances. Ictal and interictal electroencephalographic (EEG) abnormalities appeared bilaterally and multiregionally with right-sided preponderance. Magnetic-resonance imaging (MRI) revealed independent bilateral hypothalamic hamartomas, more prominently on the right side. Endoscopic surgery of the right HH was performed in each patient, resulting in a significant seizure reduction in both cases. To the best of our knowledge, there are no other reports of independent bilateral HHs in the literature.

First clinical experiences with perampanel--the Kork experience in 74 patients.

Perampanel (PER) has been approved for adjunctive treatment of partial-onset seizures in patients age 12 years and older. In Germany, PER was licensed and marketed in September of 2012. At our tertiary referral epilepsy center, a couple of difficult-to-treat patients were awaiting this introduction of PER; therefore, we were able to initiate treatment in many patients within a short period of time. For this report we collected and analyzed the data of the first patients who had been started on add-on PER between September and December of 2012, so that we were able to evaluate at least 6 months of treatment when we made this analysis. At cutoff in June of 2013, 74 patients could be analyzed. Mean age was 38.4 years (range 15-71 years). PER doses ranged from 4 to 14 mg (mean 8.8 mg). All patients took PER once daily at bedtime. Seventy-one patients had focal epileptic seizures; the remaining four patients had Lennox-Gastaut syndrome. Considering the last 3 months of observation compared with baseline, 34 patients (46%) were responders with a reduction of seizure frequency of at least 50%. Ten patients of these (14% of all) were seizure-free. Adverse events were reported in 40 patients (54%). Leading side effects were somnolence (n = 31, 42%) and dizziness (n = 13, 18%), followed by ataxia, irritability, falls, cognitive slowing, and depression in single cases. Six-month retention rate was 70%. Our first clinical experiences with add-on PER in a highly selected group of difficult-to-treat epilepsies are promising.

Is routine electroencephalography (EEG) a useful biomarker for pharmacoresistant epilepsy?

People with seizure disorders who have been treated at the Kork Epilepsy Center over a prolonged time period and who thus provide data concerning the chronic course of epilepsy were investigated in order to address the potential role of electroencephalography (EEG) as a biomarker for pharmacoresistant epilepsy. Clinical course and the corresponding findings from their first recorded EEG, their first EEG following appropriate treatment, and their last EEG were compared. Furthermore, we investigated if interictal epileptiform discharges (IEDs) differ in amplitude and morphology if recorded in long-term seizure-free patients. The early cessation of IEDs was a relatively good marker for a good prognosis, especially in idiopathic generalized epilepsies. However, persistent IEDs had no major impact on the long-term prognosis. We found no differences between IEDs in seizure-free patients or patients with ongoing seizures. Therefore, in our hands, routine EEG was not an appropriate biomarker for the prediction of pharmacoresistant epilepsy. Additional factors such as etiology and pathophysiology also need to be considered.

Hypothalamic hamartoma: is the epileptogenic zone always hypothalamic? Arguments for independent (third stage) secondary epileptogenesis.

Gelastic seizures associated with hypothalamic hamartomas (HHs) are a clinicoradiologic syndrome presenting with a variety of symptoms, including pharmacoresistant epilepsy with multiple seizure types, electroencephalography (EEG) abnormalities, precocious puberty, behavioral disturbances, and progressive cognitive deterioration. Surgery in adults provides seizure freedom in only one third of patients. The poor results of epilepsy surgery could be explained by an extrahypothalamic epileptogenic zone. The existence of an independent, secondary epileptogenic area with persistent seizures after resection of the presumably primary lesion supports the concept of a "hypothalamic plus" epilepsy. "Hypothalamic plus" epilepsy could be related to either an extrahypothalamic structural lesion (visible on magnetic resonance imaging [MRI] or on neuropathology) or if the former is absent, to a functional alteration with enhanced epileptogenic properties due to a process termed secondary epileptogenesis. We report two patients with gelastic seizures with HH (gelastic seizures isolated or associated with dyscognitive seizures of temporal origin). Both patients underwent two-step surgery: first an endoscopic resection of the HH, followed at a later time by temporal lobectomy. Both patients became seizure-free only after the temporal lobectomy. In both cases, neuropathology failed to demonstrate a significant structural lesion in the temporal lobe. To our knowledge, for the first time, these two cases suggest the existence of independent secondary epileptogenesis in humans.

"Plok-plok" syndrome: Posttraumatic stress disorder following an SEEG thermocoagulation and direct electrical stimulation procedure.

The psychological impact of intracerebral electroencephalography (stereoelectroencephalography [SEEG]) including the thermocoagulation procedure has not yet been clearly studied. We present a case of a patient who, following an SEEG procedure for presurgical evaluation of intractable focal epilepsy, developed severe symptoms of posttraumatic stress disorder. Such an occurrence may be under-estimated. Perceived traumatic exposure during SEEG and the development of posttraumatic psychological symptoms should be further studied in order to define risk factors and to improve the monitoring and psychological management of patients during their hospitalization. A careful and systematic procedure of prevention and support before, during, and after SEEG could decrease the risk of development or worsening of symptoms of anxiety, depression, and posttraumatic stress disorder.

Hyperkinetic seizures in patients with temporal lobe epilepsy: clinical features and outcome after temporal lobe resection.

PURPOSE: Temporal lobe epilepsy (TLE) is usually associated with automatisms. Hyperkinetic seizures are supposed to be unusual. Because we witnessed several patients with TLE and ictal hyperkinetic symptoms, we retrospectively assessed the number, clinical findings, and seizure outcome in such patients who had undergone temporal lobe resection. METHODS: We reviewed medical history, video-electroencephalography (EEG) recording and neuroimaging of adult patients who underwent epilepsy surgery for TLE at the Kork Epilepsy Center over the last 20 years with a minimum postoperative follow-up of 12 months. KEY FINDINGS: Among 294 patients who were resected exclusively in the temporal region, we identified 17 (6%) who presented with hyperkinetic semiology such as violent vocalization, complex movements of the proximal segments of the limbs, rotation of the trunk, pelvic thrusting, or early tonic or dystonic posturing. Most of the patients had a preceding aura. Ictal EEG activity was located in the corresponding temporal region, usually with a wide distribution over temporal electrodes with fast spread to unilateral frontal electrodes and to the contralateral side. Neuroimaging revealed extended lesions in the temporal lobe involving mesial and neocortical structures. Most of the patients underwent classical anterior temporal lobe resection including amygdalo-hippocampectomy. Fourteen patients (82%) became completely seizure-free (Engel class Ia). Histopathology showed mainly focal cortical dysplasia plus hippocampal sclerosis. SIGNIFICANCE: Hyperkinetic seizure semiology may occasionally occur in patients with TLE and is, therefore, no contradiction to the hypothesis of TLE if scalp EEG patterns and neuroimaging findings correspond. The postoperative seizure outcome is favorable in such patients and not different from outcome data in classical TLE.

Gelastic seizures and the hypothalamic hamartoma syndrome: Epileptogenesis beyond the lesion?

The clinicoradiologic syndrome of hypothalamic hamartoma (HH) manifests with a variety of symptoms, including pharmacoresistant epilepsy with multiple seizure types, precocious puberty, behavioral disturbances, and cognitive impairment. Gelastic seizures are an early marker of epilepsy with HH in most of the cases. Despite a high variability, two major epilepsy phenotypes can be distinguished, based on electroclinical features: (i) focal seizures with epigastric or déjà-vu aura, loss of consciousness, and oroalimentary or gestural automatisms suggestive of temporal lobe involvement; and (ii) motor seizures with tonic, atonic, myoclonic, or versive phenomena, suggesting frontoparietal network involvement, with possible evolution toward an epileptic encephalopathy. The underlying physiopathologic mechanisms are not completely elucidated. The well-known intrinsic epileptogenicity of the HH represents the rationale for direct HH-aiming surgical procedures, with variable success in achieving seizure freedom. The concept of kindling-like secondary epileptogenesis has been suggested as a possible putative mechanism since the very beginnings of the hamartocentric era. Accordingly, a cortical area with enhanced epileptogenic properties due to an independent stage of secondary epileptogenesis would be responsible for seizures persisting after hamartoma ablation. However, recent intracerebral stereotactic EEG (SEEG) explorations demonstrated more complex, both reciprocal and hierarchical, relationships within the hypothalamo-cortical epileptogenic networks. Network formation may be due to either secondary epileptogenesis or widespread epileptogenicity present at the outset. A short time window from epilepsy onset to surgery seems to be crucial to cure epilepsy by direct surgery addressing a hamartoma. SEEG exploration may be reasonably proposed in cases where clinical data suggest an extension of the epileptogenic zone outside the limits of the HH, especially in focal seizures with impaired awareness and absence of gelastic seizures, or after a failure of the direct HH-aiming procedure.

VEP atlas: An anatomic and functional human brain atlas dedicated to epilepsy patients.

BACKGROUND: Several automated parcellation atlases of the human brain have been developed over the past decades, based on various criteria, and have been applied in basic and clinical research. NEW METHOD: Here we present the Virtual Epileptic Patient (VEP) atlas that offers a new automated brain region parcellation and labeling, which has been developed for the specific use in the domains of epileptology and functional neurosurgery and is able to apply at individual patient's level. RESULTS: It comprises 162 brain regions, including 73 cortical and 8 subcortical regions per hemisphere. We demonstrate the successful application of the VEP atlas in a cohort of 50 retrospective patients. The structural organization is complemented by the functional variation of stereotactic intracerebral EEG (SEEG) signal data features establishing brain region-specific 3d-maps. COMPARISON WITH EXISTING METHODS: The VEP atlas integrates both anatomical and functional definitions in the same atlas, adapted to applications for epilepsy patients and individualizable. CONCLUSION: The covariation of structural and functional organization is the basis for current efforts of patient-specific large-scale brain network modeling exploiting virtual brain technologies for the identification of the epileptogenic regions in an ongoing prospective clinical trial EPINOV.

Anatomical electroclinical correlations during an SEEG-recorded seizure with autoscopic hallucination.

Autoscopic phenomena (AP) are characterized by seeing an image of oneself in extra-personal space. These phenomena are rare and the anatomy of brain regions producing these phenomena is not well defined. We report anatomical electroclinical correlations during a stereoelectroencephalography-recorded seizure with autoscopic hallucination (a form of AP in which the double of oneself is seen from an internal point of view). Seizure onset zone was quantified using the epileptogenicity index method (EI). Maximal EI values were obtained in the left lateral parietal cortex (supramarginal gyrus) and high values were also found in the left posterior-superior insular cortex, left temporo-occipital junction and contralateral inferior parietal lobule. Our case confirms the involvement of the inferior parietal lobule, temporo-parieto-occipital junction and posterior insula in the genesis of autoscopic hallucination.

Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia.

Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients' movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.

Comparison of Functional Deficit Zone Defined by FDG PET to the Epileptogenic Zones Described in Stereo-Electroencephalograph in Drug-Resistant Epileptic Patients Treated by Surgery.

INTRODUCTION: The purpose of presurgical assessment is to delimit the epileptogenic zone and the functional deficit zone with a brain MRI, an electroencephalograph or even a stereo-electroencephalograph (SEEG), neuropsychological evaluation, and a cerebral FDG PET. Several studies concur that the hypometabolism of FDG PET seems to be consistent with epileptogenic zones. We compared the functional deficit zone defined by FDG PET with the results of the SEEG, for each cluster electrode contact (CEC) located in the gray matter. METHODS: The electrode diagram of the 15 patients (486 CECs) operated on for drug-resistant epilepsy was merged with MRI and FDG PET. The metabolisms of FDG PET and SEEG were compared using a logistic regression test. RESULTS: The presence of hypometabolism resulted in a significantly higher risk of being in the seizure onset zone and the irritative zone, particularly when it was intense. Of the deeply hypometabolic CECs, 47% were in the seizure onset zone and 76% in the irritative zone. Normal metabolism resulted in a significantly higher probability of being in the healthy zone. CONCLUSIONS: This study demonstrated an association between the presence of normal metabolism and the location of CECs in the healthy zone, and between the presence of pathological metabolism and the location of CECs in the seizure onset zone and the irritative zone, with metabolism abnormalities progressively more present and more intense near the seizure onset zone.

High-frequency oscillations and spikes running down after SEEG-guided thermocoagulations in the epileptogenic network of periventricular nodular heterotopia.

OBJECTIVE: Epilepsy associated with periventricular nodular heterotopia (PNH) is characterized by complex relationships between the heterotopic and the normotopic cortex during the interictal state and at seizure onset. High-frequency oscillations (HFO) have been proposed as a marker of epileptogenicity that might reflect disease activity. The effects of thermocoagulations on epileptogenicity in this context remain unknown. We aimed to investigate the interictal HFO- and spike profiles of different cortical structures before and after two consecutive SEEG-guided thermocoagulations, in correlation with seizure outcome, in a patient with PNH-related drug-resistant epilepsy. METHODS: The epileptogenic zone (EZ) was defined by SEEG analysis based on the Epileptogenicity Index. Interictal spikes, ripples (80-250 Hz) and fast ripples (FR, 250-330 Hz) were analyzed within the heterotopia, the temporal neocortex and the hippocampus. RESULTS: The SEEG recordings revealed a distributed EZ involving the heterotopia and the posterior temporal neocortex. Both structures were targeted by thermocoagulations. Background spikes, ripples and FR-rates were significantly higher in PNH compared to the normotopic cortex. A drastic reduction of spikes (by over 80%) and absence of FR were demonstrated both in the PNH and in the neocortex during the second SEEG exploration 6 months after the first thermocoagulation, whereas no significant difference was observed in the posterior hippocampus. Ripples were significantly reduced by the first and suppressed by the second thermocoagulation within the three structures. Seizures relapsed after two months but decreased in frequency after the first thermocoagulation. Sustained seizure-freedom was achieved only after the second procedure. CONCLUSIONS: Our data demonstrate the running down of interictal HFO and spikes within the epileptogenic network following thermocoagulations of heterotopic and normotopic sites involved at seizure onset. This dynamics was in good correlation with significantly improved seizure control. SIGNIFICANCE: Combination of ictal and different interictal markers of epileptogenicity, including HFO and spike analysis, is important to get the full picture of the epileptogenic zone and could help to evaluate the disease activity.

Can histologically normal epileptogenic zone share common electrophysiological phenotypes with focal cortical dysplasia? SEEG-based study in MRI-negative epileptic patients.

OBJECTIVE: We aimed to assess stereoelectroencephalography (SEEG) seizure-onset and interictal patterns associated with MRI-negative epilepsy and investigate their possible links with histology, extent of the epileptogenic zone (EZ) and surgical outcome. METHODS: We retrospectively analysed a cohort of 59 consecutive MRI-negative surgical candidates, who underwent SEEG recordings followed by cortectomy between 2000 and 2016. RESULTS: Most of the eight distinct seizure-onset patterns could be encountered both in confirmed focal cortical dysplasia (FCD) and in histologically non-specific or normal cases. We found strong correlation (p = 0.008) between seizure-onset pattern and histology for: (1) slow-wave/DC-shift prior to low voltage fast activity (LVFA), associated with normal/non-specific histology, and (2) bursts of polyspikes prior to LVFA, exclusively observed in FCD. Three interictal patterns were identified: periodic slow-wave/gamma burst, sub-continuous rhythmic spiking and irregular spikes. Both "periodic" patterns were more frequent in but not specific to FCD. Surgical outcome depended on the EZ complete removal, regardless electrophysiological features. CONCLUSIONS: Histologically normal and FCD-associated epileptogenic zones share distinct interictal and ictal electrophysiological phenotypes, with common patterns between FCD subtypes and between dysplastic and apparently normal brain. SIGNIFICANCE: Some specific seizure-onset patterns seem to be predictive of the underlying histology and may help to detect an MRI-invisible FCD.